Nuclear receptor NHR-49 promotes peroxisome proliferation to compensate for aldehyde dehydrogenase deficiency inC. elegans

Abstract

The intracellular level of fatty aldehydes is tightly regulated to minimize the formation of toxic aldehyde adducts of cellular components. Accordingly, deficiency of a fatty aldehyde dehydrogenase FALDH causes the neurologic disorder Sjögren-Larsson syndrome (SLS) in humans. However, cellular responses to unresolved, elevated fatty aldehyde levels are poorly understood. Based on lipidomic and imaging analysis, we report that the loss of endoplasmic reticulum-, mitochondria- and peroxisomes-associated ALH-4, the C. elegans FALDH ortholog, increases fatty aldehyde levels and reduces fat storage. ALH-4 deficiency in the intestine, cell-nonautonomously induces NHR-49/NHR-79-dependent hypodermal peroxisome proliferation. This is accompanied by the upregulation of catalases and fatty acid catabolic enzymes, as indicated by RNA sequencing. Such a response is required to counteract ALH-4 deficiency since alh-4; nhr-49 double mutant animals are not viable. Our work reveals unexpected inter-tissue communication of fatty aldehyde levels, and suggests pharmacological modulation of peroxisome proliferation as a therapeutic strategy for SLS.

The endoplasmic reticulum-resident protein TMEM-120/TMEM120A promotes fat storage in C. elegans and mammalian cells

“…1A and C). Similar results were observed when we used DHS-3::mRuby as a fluorescent LD marker (Zeng et al, 2020) (Fig. 1F).…”

“…Upper organic phase was collected after centrifugation and combined with those previously collected. Extracts were dried under a stream of nitrogen at room temperature, redissolved in 200µl acetonitrile (RCI Labscan, for HPLC)/ isopropanol (RNH)/ water(65/30/5, v/v/v) and stored at -80 o C. Lipid analysis was performed as previously described (Zeng et al, 2020). A 100µl aliquot was analyzed using the Bruker Elute UPLC system with 2 technical injections per sample.…”